This invention relates to a parenteral form of application of thalidomide and to a method of producing it.
The excessive formation of the cytokinin TNF-a (tumour necrosis factor a) plays a central part in the pathogenesis of graft-versus-host syndrome, aphthous stomatitis, erythema nodosum leprosum, morbus Boeck, morbus Crohn, rheumatoid arthritis and a series of other diseases which are associated with inflammatory symptoms. The basis for the therapy of these diseases consists of the targeted suppression of the release of TNF-a, by administering immunomodulating active ingredients, such as dexamethasone or thalidomide for example. While injectable forms of corticoids such as dexamethasone exist, this has hitherto not been the situation for thalidomide.
In the treatment of aphthous stomatitis, thalidomide has been shown to be superior to classical immunosuppressants. Examples of diseases in which thalidomide has exhibited good efficacy without resulting in a general immunosuppression include cutaneous lupus erythematosus, pyoderma gangrenosum and orogenital ulcers with morbus Behcet, as well as ulcerations in HIV-infected patients, which do not differ histologically from aphthous ulcers and in which--in contrast to the majority of HIV-associated mucocutaneous lesions--no microbial instigators can be detected. As distinct from stomatitis aphthosa, these lesions, which can be characterized as major aphthae, can occur in the entire digestive tract, and when located in the pharyngeal space or the esophagus make the absorption of food difficult, and also make the taking of oral medication difficult, due to the pain which they cause. The pathogenetic factors are endogenous mediators which have effects on the endothelium and on circulating leukocytes. Under the influence of locally-formed TNF-a and other cytokinins, there is a marked increase in the adhesiveness of the endothelium in relation to leukocytes, which makes a definitive contribution to the development of venous vasculitis. Substances which, like thalidomide, suppress this alteration of the endothelium without at the same time blocking the specific cellular immune defense, can constitute an important advance in therapy.
In severe cases of pharyngeal or esophageal ulcers, in which the taking of oral medication is made difficult, or in which this may even be impossible, and in cases of HIV-associated pathology in which severe symptoms of diarrhoea make the use of oral medication unpredictable, it is appropriate to administer active ingredients parentally. However, the low solubility of thalidomide in water (0.012 mg/ml; Arch. Pharm. 321, 371 (1988)) constitutes an obstacle to the parenteral administration of this active ingredient. There has, therefore, been no lack of attempts to develop water-soluble forms of administration.
Water-soluble thalidomide derivatives are known from DE 4,211,812. These thalidomide derivatives have a considerably higher solubility in water than that of thalidomide and are suitable for parenteral administration.
In addition, thalidomide prodrugs have been proposed for parenteral application which can be administered in water-soluble form in the physiological pH range and which are toxicologically harmless (DE 19,613,976). A disadvantage here is that both types of the aforementioned compounds involve higher production costs than the costs for the production of thalidomide.